Global Study Explores RAF/MEK/FAK Combo in Recurrent LGSOC, With or Without KRAS Mutations

Susana K. Banerjee, PhD

An international study of the small molecule RAF/MEK inhibitor alone and in combination with the FAK inhibitor defactinib has raised excitement following the FDA’s breakthrough therapy designation to the novel combination for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC).

The phase 2 ENGOT-ov60/GOG3052/RAMP 201 trial (NCT04625270) is now recruiting patients with recurrent LGSOC in 26 locations across the United States and the United Kingdom. To be eligible for the study, patients are required to have histologically proven LGSOC, a KRAS mutation or KRAS wildtype if treated in the first part of the study, measurable disease per RECIST v1.1, an ECOG performance status of 1 or lower, and adequate organ function and recovery from prior toxicities.

In an interview with Targeted Oncology™ following a presentation of the study protocol at the 2021 American Society of Clinical Oncology Annual Meeting, Susana K. Banerjee, PhD, a consultant medical oncologist and research lead for the Gynaecology Unit at The Royal Marsden NHS Foundation Trust, explained the progress of ENGOT-ov60/GOG3052/RAMP 201 in detail.

TARGETED ONCOLOGY™: What does the treatment landscape look like for recurrent LGSOC currently?

BANERJEE: This is a very rare type of gynecological cancer, and unfortunately, current approved treatments for recurrent or advanced disease are not as effective as we need them to be. For example, chemotherapy, with response rates in this setting are less than 10% and hormonal therapy, for example, letrozole is around that mark or slightly higher. But there has been progress in developing MEK inhibitors in this setting, and they have shown efficacy.

I was very pleased to have been involved recruiting patients to 2 different randomized trials as a site at the Royal Marsden in London in the UK. These trials included the MILO/ENGOT-ov11 trial of binimetinib [Mektovi] versus standard of care and the GOG-0281 trial of trametinib [Mekintist] versus standard of care. What is clear is that some patients can benefit more than without conventional treatments for MEK inhibitors.

Another important point as we're understanding a lot more about the biology of LGSOC is that around 30% of these patients may harbor a mutation in the KRAS gene, and up to around 70% may have alterations in the RAS pathway. So, that's where we are at at the moment.

Can you describe the mechanism of action for this VS-6766? What was the rationale for administering this agent in combination with defactinib to patients with recurrent LGSOC?

VS-6766 is a unique small molecule inhibitor, and it blocks MEK kinase activity and RAF phosphorylation of MEK. This has the potential to eliminate any compensatory MEK activation. Defactinib is an ATP competitive, reversible inhibitor of FAK and this has been shown to block some compensatory parallel signaling observed when there's RAS pathway blockade. So, there is preclinical data that indicates that FAK inhibition can induce tumor regression when combined with RAF/MEK inhibitors in in vivo models of KRAS-mutated ovarian cancer.

What’s really exciting is that the combination of VS-6766 and defactinibis currently being evaluated in the ongoing investigator-sponsored frame study. This is an early-phase academic study sponsored by the Institute of Cancer Research in the UK, and early results have been reported. Responses were noted in patients with recurrent LGSOC, particularly those with KRAS mutations. Activity was also seen in patients that had previously been treated with a MEK inhibitor, so this is very exciting. The response rates that we presented [among] small numbers in an early phase study was 56% in KRAS-mutated patients, and in the overall population of patients with LGSO, it was around 40%.

We plan to present an update of this study at a congress later this year.

A new phase 2 study is underway in this patient population. Can you discuss the study design?

Given these encouraging preclinical results seen so far, the ENGOT-ov60/GOG3052/RAMP 201 trial will be a phase 2 study investigating the combination in this setting. It's adaptive in design and is a2-part multicenter study with parallel cohorts, which are randomized and open label. The study is designed to evaluate both the efficacy and of course safety of either VS-6766alone or in combination with defactinib.

What's important is that the cohorts are according to KRAS mutation status. This will be very important in assessing the activity up front in patients with a KRAS mutation or without. I think this is very exciting place that we're in at the moment.

What are the key goals of this study?

The primary end point is looking at overall response rate, and it's by a Blinded Independent Radiological Review. But there are very important secondary end points looking at safety, tolerability, other clinical outcomes such as progression-free survival and overall survival. Importantly, we'll be looking at the pharmacokinetics here, and of course, biomarkers of activity. The goal is to establish whether this combination has meaningful activity for patients in a setting where current approved therapies need to be better.

We will also be looking, as I say, for the first time up front at the activity according to KRAS mutation status, and the hope is that this combination will be helpful going forward.

This trial is open already in the US and recruiting. We hope to be opening in European countries like the UK, France, Spain, Belgium, Italy, and Canada very shortly. I think what's important in terms of the inclusion criteria is that patients need to have had disease progression after at least 1 prior therapy containing platinum. Importantly, patients that have had prior MEK inhibitor treatments are permitted to enter this study.

Finally, the good news about this study is the FDA breakthrough designation was granted in May to VS-6766 in combination with defactinib for the treatment of recurrent LGSOC after at least 1 prior platinum-containing therapy. So, I'm excited about this collaboration, and I'm very much looking forward to recruiting patients into this trial. I really hope that it can help shape the future treatments for women with LGSOC.

In the case that this trial is positive in the future, what do you think the impact will be?

There is great potential of targeted therapies and I very much hope for more approved therapies by the FDA, EMA, and worldwide so that women with this rare malignancy have effective treatment options.

I've talked about this trial in recurrent LGSOC. Of course, it would be great, in general, for effective treatments to be brought earlier on in the disease pathway at diagnosis, and ultimately, we would like to prevent this disease.

_Reference:

_{Banerjee SN, Monk BJ, Nieuwenhuysen EV, et al. ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2021;39(suppl 15). doi: 10.1200/JCO.2021.39.15_suppl.TPS5603}